- FURTHER STUDIES ON THE SYNTHESIS OF α-FLUORO CARBONYL COMPOUNDS
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The trimethylsilyl enol ethers of cycloalkanones and acid esters are converted in high yields (70-90percent) to the corresponding α-fluoro carbonyl derivative using XeF2 in CH2Cl2.Non-cyclic α-hydroxy ketones such as ethyl mandelate are efficiently transformed to the α-fluoro product by DAST and by Ishikawa's reagent.Nucleophilic displacement of halogen by fluoride failed in cyclic systems, giving instead, α,β-unsaturated ketones in DMF or CH3CN (18-crown-6) and 1,2-diones in DMSO, with KF acting as a base.Attempts at DMSO oxidation of I(Br)F adducts failed to give the α-fluoro ketones, but resulted in dehydrohalogenation to the trans-vinyl fluorides.
- Cantrell, Gary L.,Filler, Robert
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- AZABICYCLO AND DIAZEPINE DERIVATIVES FOR TREATING OCULAR DISORDERS
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The present invention provides in one aspect azabicycio and diazepine derivatives useful as modulators of muscarinic receptors. In another aspect, the present invention provides pharmaceutical compositions for treating ocular diseases, the compositions comprising at least one muscarinic receptor modulator. Formulae (I) & (II):
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Page/Page column 20-21
(2019/05/22)
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- Synthesis of 18F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [18F]fluoride
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Herein, we report the radiosynthesis of 18F-difluoromethylarenes via the assembly of three components, a boron reagent, ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [18F]fluoride. The two key steps are a copper-catalysed cross-coupling reaction, and a Mn-mediated 18F-fluorodecarboxylation.
- Sap, Jeroen B. I.,Wilson, Thomas C.,Kee, Choon Wee,Straathof, Natan J.W.,Ende, Christopher W.am,Mukherjee, Paramita,Zhang, Lei,Genicot, Christophe,Gouverneur, Véronique
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p. 3237 - 3241
(2019/03/21)
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- Catalytic decarboxylative fluorination for the synthesis of Tri- and difluoromethyl arenes
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Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [18F]labeling is demonstrated using [ 18F]Selectfluor bis(triflate), a reagent affording [ 18F]tri- and [18F]difluoromethylarenes not within reach with [18F]F2.
- Mizuta, Satoshi,Stenhagen, Ida S.R.,O'Duill, Miriam,Wolstenhulme, Jamie,Kirjavainen, Anna K.,Forsback, Sarita J.,Tredwell, Matthew,Sandford, Graham,Moore, Peter R.,Huiban, Mickael,Luthra, Sajinder K.,Passchier, Jan,Solin, Olof,Gouverneur, Véronique
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p. 2648 - 2651
(2013/07/11)
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- The effect of substituents and operating conditions on the electrochemical fluorination of alkyl phenylacetates in Et3N·4HF medium
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Selective electrochemical fluorination of alkyl phenylacetates (Ph-CH2-COOR, where R is methyl, ethyl, n-propyl, n-butyl, i-propyl and sec-butyl) under galvanostatic conditions were reported in Et3N·4HF medium. Preparative electrolysis experiments were carried out both in pre-electrolysed dry Et3N·4HF and the same electrolyte medium without pre-electrolysis. Very little hydrolysed fluorinated products were obtained in pre-electrolysed medium where as significant quantities of hydrolysed products leading to fluorinated phenylacetic acid were obtained from Et3N·4HF without pre-electrolysis. Under optimum experimental conditions up to 87% selectivity of monofluoro ester could be achieved. Difluoro alkyl phenylacetate, monofluoro and difluoro phenylacetic acids were the other predominant side products obtained. The hydrolysis appears to be initiated by tautomeric transformation of proton after the initial electro oxidative formation of the cation radical. 19F as well as 1H NMR spectroscopy have been employed to identify the minor constituents formed during the electro oxidative process.
- Ilayaraja,Manivel,Velayutham,Noel
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p. 185 - 192
(2008/09/17)
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- N-ALKYL-AZACYCLOALKYL NMDA/NR2B ANTAGONISTS
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Compounds represented by Formula (I): and/or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof, are effective as NMDA/NR2B antagonists useful for treating conditions such as pain, Parkinson’s disease, Alzheimer’s disease, epilepsy, depression, anxiety, ischemic brain injury including stroke.
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Page/Page column 46
(2008/06/13)
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- A novel general method for preparation of α-fluoro-α-arylcarboxylic acid. Direct fluorination of silyl ketene acetals with Selectfluor
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The reaction of an α-arylcarboxylic acid with TBSCl and LiHMDS in THF yielded bis-silyl ketene acetal, which was directly fluorinated with inexpensive Selectfluor to produce the corresponding α-fluoro-α-arylcarboxylic acid in high yield. Application of the methodology to the synthesis of α-fluorocarboxylic ester from the corresponding carboxylic ester is also described.
- Zhang, Fei,Song, Jake Z.
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p. 7641 - 7644
(2007/10/03)
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- Enantioselective hydrolysis of (RS)-2-fluoroarylacetonitriles using nitrilase from Arabidopsis thaliana
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The enzymatic resolution of 2-fluoroarylacetonitriles (RS)-3 using nitrilase from the plant Arabidopsis thaliana is described. Racemic 2-fluoronitriles 3 are easily accessible from O-silylated aromatic cyanohydrins 2 by reaction with DAST. The nitriles (RS)-3 were hydrolysed with the nitrilase as a catalyst, not to the expected 2-fluoroarylacetic acids but to the corresponding (R)-2-fluoroarylacetamides (R)-5 as the main products. After optimization of reaction conditions (pH 9, 7°C), the enantiomeric excesses of (R)-5a,c and f (R=H, 3-Me, 3-OMe) could be improved to >99% by one recrystallization. The acid catalysed hydrolysis of (R)-5a,5c and 5f afforded the corresponding (R)-2-fluoroarylacetic acids (R)-4a,4c and 4f without racemization.
- Effenberger, Franz,Osswald, Steffen
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p. 279 - 285
(2007/10/03)
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- Synthesis of 2-fluoro- acids, esters, and amides from α-dicyanoepoxides
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The opening of α-dicyanoepoxides by pyridine polyhydrofluoride yields polymerisable 2-fluorocyanoformyls which may be kept intact when diluated in dichloromethane or ether. These intermediates react with nucleophiles such as water, methanol or amines to give respectively 2-fluoroacids, esters or amides.
- Amanetoullah, A. Ould,Chaabouni,Baklouti
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p. 1155 - 1161
(2007/10/03)
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- Electrolytic Reactions of Fluoro Organic Compounds. 7. Anodic Methoxylation and Acetoxylation of 2,2,2-Trifluoroethyl Sulfides. Preparation of Highly Useful Trifluoromethylated Building Blocks
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Anodic methoxylation and acetoxylation of 2,2,2-trifluoroethyl sulfides and the corresponding nonfluorinated sulfides were comparatively studied.It was found that a trifluoromethyl group remarkably promoted anodic substitution and methoxy and acetoxy groups were introduced adjacent to the trifluoromethyl group of the sulfides.Longer perfluoroalkyl groups also promoted these anodic substitutions.These products were shown to be highly useful building blocks fro the synthesis of fluoro organic compounds.
- Fuchigami, Toshio,Yamamoto, Kayoko,Nakagawa, Yuki
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p. 137 - 142
(2007/10/02)
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- The in situ generation and trapping of some fluorine-substituted ketenes
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Fluoroketene, difluoroketene, methylfluoroketene, trifluoromethylfluoroketene, and phenylfluoroketene were each generated, in situ, via dehydrohalogenation of the respective acid chlorides. In the presence of cyclopentadiene [2 + 2] adducts were obtained in all but the difluoroketene case. In the absence of cyclopentadiene, low temperature 19F nmr indicated the presence of acyl ammonium salts and enolates, potential precursors of the ketenes, but no actual ketene species could unambiguously be detected. The stereochemical results were consistent with the currently accepted steric-based mechanistic rationale for stereochemical determination in ketene cycloadditions.
- Dolbier Jr., William R.,Lee, Suk Kyu,Phanstiel IV, Otto
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p. 2065 - 2072
(2007/10/02)
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- Power and structure-variable fluorinating agents. The N-fluoropyridinium salt system
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The usefulness of the N-fluoropyridinium salt system as a source of fluorinating agents was examined by using substituted or unsubstituted N-fluoropyridinium triflates 1-11, N-fluoropyridinium salts possessing other counteranions 1a-d and 3a, and the counteranion-bound salts, N-fluoropyridinium-2-sulfonates 12 and 13. Electrophilic fluorinating power was found to vary remarkably according to the electronic nature of the ring substituents. This power increased as the electron density of positive nitrogen sites decreased, and this was correlated to the pKa values of the corresponding pyridines. By virtue of this variation, it was possible to fluorinate a wide range of nucleophilic substrates differing in reactivity. It is thus possible to fluorinate aromatics, carbanions, active methylene compounds, enol alkyl or silyl ethers, vinyl acetates, ketene silyl acetals, and olefins through the proper use of salts pentachloro 6 through 2,4,6-trimethyl 2, their power decreasing in this order. All the reactions could be explained on the basis of a one-electron-transfer mechanism. N-Fluoropyridinium salts showed high chemoselectivity in fluorination, the extent depending on the reactive moiety. In consideration of these Findings, selective 9α-fluorination of steroids was carried out by reacting 1 with tris(trimethylsilyl ether) 73 of a triketo steroid. Regio- or stereoselectivity in fluorination was determined by a N-fluoropyridinium salt structure. Steric bulkiness of the N-F surroundings hindered the ortho fluorination of phenols and aniline derivatives, while the capacity for hydrogen bonding on the part of the counteranions prompted this process, and the counteranion-bound salts 12 and 13 underwent this fluorination exclusively or almost so. Both bulky N-fluoropyridinium triflates 2 and 7 preferentially attacked the 6-position of the conjugated vinyl ester of a steroid from the unhindered β-direction to give a thermally unstable 6β-fluoro isomer. On the basis of these results, N-fluoropyridinium salts may be concluded to constitute a system that can serve as a source of the most ideal fluorinating agents for conducting desired selective fluorination through fluorinating capacity or structural alteration.
- Umemoto, Teruo,Fukami, Shinji,Tomizawa, Ginjiro,Harasawa, Kikuko,Kawada, Kosuke,Tomita, Kyoichi
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p. 8563 - 8575
(2007/10/02)
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- Reactivite des fluorosilyloxirannes
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Fluorosilyloxiranes have been studied.Ring opening is observed in protic medium (CF3COOH, HF-pyridine) but organometallic reagents associated with Lewis acid do not react. α-Fluorocarbanions are generated from the corresponding organosilicon compounds by the nucleophilic assistance of a catalytic amount of fluoride ion.Fluoroepoxyalcohols and fluoroglycidic acids were obtained.
- Dubuffet, Thierry,Sauvetre, Raymond,Normant, Jean-F.
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p. 677 - 682
(2007/10/02)
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2-Fluoro-2-phenyl acetic acid was synthetized from phenylglycine through a fluorodeamination reaction in a HF : pyridine mixture or from ethylmandelate through fluorodehydroxylation using the reagent fluoroamine (FAR). The specific rotation of S-2-fluoro-2-phenyl acetic acid is [α] 20D = + 153° in chloroform at concentration c = 1,25 g/100 ml. This acid can be used as a derivatizing chiral agent : the enantiomers can be distinguished and the enantiomeric excess of secondary alcohols can be determined by 19F NMR spectra of the corresponding esters.
- Hamman,Barrelle,Tetaz,Beguin
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- Synthesis of α-fluorocarbonyl compounds
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Process for preparing an organic compound of the formula R2 R2 CFC(O)R3, which process comprises contacting and reacting in a reaction mixture which includes an inert solvent, at a temperature of -40° C. to -100° C., ROF and STR1 R is polyfluoroperhaloalkyl of 1-6 carbon atoms or FOCF2 ; R1 is hydrocarbyl of 1-6 carbon atoms; each R2 is selected from H, alkyl of 1-17 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl and such alkyl, cycloalkyl, aryl and heteroaryl substituted by halogen or alkoxy of 1-6 carbon atoms; R3 is selected from H, alkyl and haloalkyl of 1-16 carbon atoms, cycloalkyl of 3-10 carbon atoms, aryl and haloaryl, OSi(R1)3, OH, NH2, alkoxy of 1-6 carbon atoms, aryloxy, NHR1 and NR12 wherein R1 is alkyl of 1-6 carbon atoms, N-arylamino and nitrogen or sulfur heterocyclic of 4-5 carbon atoms; R3 and one R2 taken together is a diradical which with the C=C group is carbocyclic, heterocyclic or haloheterocyclic, and recovering from the reaction mixture the compound of the formula R2 R2 CFC(O)R3.
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